The long-term objective of this project is to develop new nucleoside analogues with antiviral activity. Although numerous antiviral drugs are already available to treat a range of viral infections, viruses rapidly mutate and become resistant to existing drugs and treatments. New antiviral drugs are therefore in constant demand to control viral diseases, which pose a significant threat to public health. The discovery of new nucleoside analogues is currently limited by a lack of different nucleobases. We hypothesize 1,4-disubstituted 1,2,3- triazoles should be able to serve as a nucleobase scaffold that will be useful for the discovery of new antiviral nucleoside analogues. A triazole ring should effectively link a sugar and functional groups involved in Watson- Crick base pairing. The resulting assembly of a sugar, triazole, and H-bonding groups will then constitute a nucleoside analogue. The first aim of our proposal is to develop proof-of-principle examples that will match fully functionalized triazoles with a very simple sugar chain. Triazoles will be formed by cycloadditions of protected glycosyl azides with an enol ether. Necessary functional groups for Watson-Crick base pairing will then be installed. Watson-Crick functionality will generally imitate the H-bond acceptor/donor/donor pattern of guanine. Deprotection of the sugar chain will complete the synthesis. Once the synthetic methods have been fully established, we will move to the second aim. The second aim of the proposal is to prepare true triazole- based nucleoside analogues. The sugars of the glycosyl azides will correspond to sugars used in FDA- approved nucleoside analogues. Specifically targeted sugars include those found in acyclovir, penciclovir, and abacavir. The third aim strives to test the new compounds for antiviral activity and cytotoxicity. Antiviral testing will primarily be performed through the NIAID's Antimicrobial Acquisition and Coordinating Facility. Cytotoxicity testing will be performed in collaboration with Professor David Wessner of the Biology Department of Davidson College. PUBLIC HEALTH RELEVANCE: This project strives to develop a new method for making antiviral drugs and to test all new drugs for biological activity. The drugs of interest resemble nucleic acids, the building blocks of genetic material in organisms. Viral diseases, including AIDS, herpes, and certain types of hepatitis, are often treated with drugs that can imitate nucleic acids.